Technological strategies to estimate and control diffusive passage times through the mucus barrier in mucosal drug delivery

Abstract

In mucosal drug delivery, two design goals are desirable: 1) insure drug passage through the mucosal barrier to the epithelium prior to drug removal from the respective organ via mucus clearance; and 2) design carrier particles to achieve a prescribed arrival time and drug uptake schedule at the epithelium. Both goals are achievable if one can control "one-sided" diffusive passage times of drug carrier particles: from deposition at the mucus interface, through the mucosal barrier, to the epithelium. The passage time distribution must be, with high confidence, shorter than the timescales of mucus clearance to maximize drug uptake. For 100nm and smaller drug-loaded nanoparticulates, as well as pure drug powders or drug solutions, diffusion is normal (i.e., Brownian) and rapid, easily passing through the mucosal barrier prior to clearance. Major challenges in quantitative control over mucosal drug delivery lie with larger drug-loaded nanoparticulates that are comparable to or larger than the pores within the mucus gel network, for which diffusion is not simple Brownian motion and typically much less rapid; in these scenarios, a timescale competition ensues between particle passage through the mucus barrier and mucus clearance from the organ. In the lung, as a primary example, coordinated cilia and air drag continuously transport mucus toward the trachea, where mucus and trapped cargo are swallowed into the digestive tract. Mucus clearance times in lung airways range from minutes to hours or significantly longer depending on deposition in the upper, middle, lower airways and on lung health, giving a wide time window for drug-loaded particle design to achieve controlled delivery to the epithelium. We review the physical and chemical factors (of both particles and mucus) that dictate particle diffusion in mucus, and the technological strategies (theoretical and experimental) required to achieve the design goals. First we describe an idealized scenario - a homogeneous viscous fluid of uniform depth with a particle undergoing passive normal diffusion - where the theory of Brownian motion affords the ability to rigorously specify particle size distributions to meet a prescribed, one-sided, diffusive passage time distribution. Furthermore, we describe how the theory of Brownian motion provides the scaling of one-sided diffusive passage times with respect to mucus viscosity and layer depth, and under reasonable caveats, one can also prescribe passage time scaling due to heterogeneity in viscosity and layer depth. Small-molecule drugs and muco-inert, drug-loaded carrier particles 100nm and smaller fall into this class of rigorously controllable passage times for drug delivery. Second we describe the prevalent scenarios in which drug-loaded carrier particles in mucus violate simple Brownian motion, instead exhibiting anomalous sub-diffusion, for which all theoretical control over diffusive passage times is lost, and experiments are prohibitive if not impossible to measure one-sided passage times. We then discuss strategies to...

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“…In general, small molecules that have minimal interaction with the mucus networks (i.e. molecules with a hydrophilic surface and electrically neutral) are more likely to diffuse across the mucus barrier successfully [ 18 ].…”

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“…Design of carriers should take into account their mobility in viscoelastic mucus toward mucosa lining the inner part of the small intestine and colon. Diffusion of particles in mucus strongly depends on their diameters and adhesive interactions with molecules constituting the mucus gel [ 2 ]. Nanoparticles (i.e., particles with equivalent diameters ranging from approximately 1–100 nm [ 3 ] which do not bind to mucus by physicochemical interactions diffuse by standard Brownian motion.…”

“…Small microparticles (microparticles are defined as particles with equivalent diameters in the range from about 0.1–100 nm [ 3 ]) with diameter of the order of mucus gel pores (about 0.2 μm) which are chemically inert toward mucus experience significant hindrance from the gel mesh. Their movements are correlated with movements of mucus chains [ 2 ]. Movement of larger (>0.5 μm) microparticles which are chemically inert toward mucus depends not only on the local fluctuations of mucus chains but to a great extent on mucus movements in the larger scale.…”

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